US4767763A - Composition for achieving tumor reversion and its use in cancerology for dogs - Google Patents

Composition for achieving tumor reversion and its use in cancerology for dogs Download PDF

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Publication number
US4767763A
US4767763A US06/883,300 US88330086A US4767763A US 4767763 A US4767763 A US 4767763A US 88330086 A US88330086 A US 88330086A US 4767763 A US4767763 A US 4767763A
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cells
flask
culture
composition
dogs
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US06/883,300
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English (en)
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Roger L. E. Bocquet
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to a composition for producing tumor reversion in dogs and to the use of this composition in cancerology in dogs.
  • Tumor reversion was demonstrated by the reappearance of two well-known standard criteria in the field of cell culture, namely the reappearance of contact inhibition and the property of adhesion to glass.
  • composition is very easy to use and effectively inhibits tumor growth in dogs, thus enabling the rest of the body to utilize its own natural means (homeostatic but especially immunologic means) in order to eliminate cells which had previously been dangerous but have simply become useless.
  • this composition is characterized by the association of three chemical products: polyethylene glycol, dimethyl sulfoxide and theophylline, as produced simply by mixing in distilled water.
  • this mixture When added to a culture of cancer cells in the surrounding culture medium (cells of cloned HeLa colonies, for example), this mixture initiates the appearance of tumor reversion.
  • composition and the method of utilization of the composition will be more specifically described in the following non-limitative example.
  • a confluent layer of HeLa cells (cancer cells) in culture was treated in accordance with the invention.
  • the culture was prepared in a Falcon box having a surface area of 75 cm 2 and containing 30 ml of culture medium (MEM 2011 Eurobio) completed with 10% fetal calf-serum (SVF Eurobio).
  • the medium was subsequently renewed twice at one-week intervals and in the proportions described above. Finally, the culture was renewed each week without any further addition of the revertant composition.
  • Flask No Reference flask without any addition for checking the normal cell growth in the HeLa culture in its usual medium.
  • Flask No 6 The difference in this case was that polyethylene glycol (1.5 ml of the 10% solution) and pure dimethyl sulfoxide (0.5 ml) were added without theophylline.
  • Flask No 1 Eight days after the instant of time 0, it was already possible to distinguish a regularly ordered pattern of cells which remained attached to the glass whereas in other locations the highly disordered state of the original cells continued to exist.
  • Flask No 4 The addition of dimethyl sulfoxide had produced no change in the culture which had followed the growth process of Flask No 2 and No 3.
  • Flask No 5 The addition of theophylline had not produced any change in the culture which had followed the growth process of Flasks No 2, No 3 and No 4.
  • Flask No 6 In this flask, however, there could be observed after eight days zones of cells which had apparently undergone a reversion process in a regularly ordered pattern: these cells had remained attached to the glass in the midst of a tissue layer which was apparently in a disordered state.
  • Flask No 1 was kept. Eighteen months later, however, it was again found that the reverted cell culture had remained in the same state or so-called quiescent state, in the form of a monolayer, and limited to the edges of the flask.
  • HeLa cell layers other than the reference HeLa cell layer had been simply preserved in order to maintain the culture strain in a continuous clone.
  • the HeLa cell layer soon became a network pattern (like a wire-mesh fence).
  • the HeLa cells were finally destroyed, torn apart, disorganized, and then passed into suspension one after the other. There then remained only a tissue of reverted cells in a single layer limited to the edges of the flask.
  • the culture formed without any difficulty a new monolayer mat which became quiescent as soon as it reached the edges of the flask.
  • the experiment had taken place over a total period of 90 days and the experimental conditions amply demonstrated a constancy of reproduction of the phenomenon.
  • the experiment was discontinued after it had been considered as a proven fact that a continuous cloned colony had been established and that the reverted HeLa cells had acquired a hereditary character.
  • the revertant composition produces action on the HeLa cells in culture and results in tumor reversion in dogs.
  • This reversion is characterized by the reappearance of essential properties which had disappeared as a result of cancerous transformation and among which the following properties have been identified: contact inhibition, stronger adhesion to glass and better cohesion between the constituent cells of the cell tissue.
  • the reverting action of the composition is dependent on the association of a membrane modifier consisting of polyethylene glycol (whose molecular weight of 1000 to 6000 is indifferent) and of a revertant consisting of dimethyl sulfoxide to which is added an adjuvant, namely theophylline.
  • the proportions indicated in the first experiment constitute a basis and a mean value.
  • atoxic membrane modifier polyethylene glycol
  • atoxic membrane modifier polyethylene glycol
  • the proportion of theophylline must be kept within a fairly narrow range.
  • a proportion of theophylline fixed at 50 microliters per 30 ml of medium is an experimental standard from which it would be advisable not to stray too far by consequently keeping to a proportion of 5% ( ⁇ 2.5%) of the solution.
  • Polyethylene glycol is a neutral chemical compound which is completely free of any toxicity, which has already been employed in subcutaneous or intravenous injections, and which has never had any immediate (allergic) effect or secondary effect either in animals or in human beings.
  • Theophylline C 7 H 8 N 4 O 2 (dimethyl-1,3 xanthine) is a chemical compound which has been employed as a drug for many years. It is a diuretic, heart stimulant and bronchial vasodilator which is used in particular for attacks of asthma.
  • the DL50 of polyethylene glycol (600) is 7.8 grams/kg. Transposed to human beings (having a weight of approximately 70 kg), this would constitute a dose of 546 grams whereas the dose which is considered sufficient represents a proportion of only 1/546 of this DL50.
  • the DL50 of dimethyl sulfoxide is 12 grams/kg in the case of mice and is 20.5 grams/kg in the case of rats. This is low systemic toxicity which produces the same manifestations in all species.
  • the dose used in human beings in a single injection represents a proportion of 1/1050 of this DL50.
  • the DL50 of theophylline is 400 mg/kg in the case of mice and is 300 mg/kg in the case of rats.
  • these doses are related to the maximum therapeutic dose employed in human subjects, that is, 0.02 gram of pure theophylline for a single injection of 10 ml of product, this dose represents a proportion of only 1/1225 of the mean DL50 of 350 mg/kg.
  • Theophylline 3 ml of the ordinary 6% pharmaceutical solution.
  • composition in accordance with the invention therefore retains the same characteristics in vivo in dogs.
  • the distilled water is replaced by physiological serum or by Quinton serum.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
US06/883,300 1982-01-29 1986-07-07 Composition for achieving tumor reversion and its use in cancerology for dogs Expired - Fee Related US4767763A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8201397 1982-01-29
FR8201397A FR2520619A1 (fr) 1982-01-29 1982-01-29 Composition revertante basee sur l'association polyethylene glycol-dimethylsulfoxyde-theophylline et son emploi en cancerologie

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US06694898 Continuation 1985-01-25

Publications (1)

Publication Number Publication Date
US4767763A true US4767763A (en) 1988-08-30

Family

ID=9270449

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/883,300 Expired - Fee Related US4767763A (en) 1982-01-29 1986-07-07 Composition for achieving tumor reversion and its use in cancerology for dogs

Country Status (8)

Country Link
US (1) US4767763A (en))
EP (1) EP0086122B1 (en))
JP (1) JPS58146510A (en))
CA (1) CA1188226A (en))
DE (2) DE86122T1 (en))
FR (1) FR2520619A1 (en))
IL (1) IL67748A (en))
ZA (1) ZA83396B (en))

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996007420A1 (en) * 1994-09-03 1996-03-14 The University Of Nottingham Macrophage stimulating composition comprising a non-ionic surfactant

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008308473A (ja) * 2007-06-18 2008-12-25 Japan Health Science Foundation 癌治療剤
FR3012037B1 (fr) * 2013-10-23 2016-05-20 Herve Edouard Henri Jeambourquin Solution révertante à base de diméthylsulfoxyde et de polyéthylène-glycol

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA824650A (en) * 1969-10-07 Desjardins Roger Suppository
GB1043012A (en) * 1964-07-28 1966-09-21 Ici Ltd Pharmaceutical compositions comprising tumour-growth-inhibitory agents

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Carter et al., Chemotherapy of Cancer, 2nd Ed., 1981, Wiley & Sons, N.Y., N.Y., pp. 26 43. *
Carter et al., Chemotherapy of Cancer, 2nd Ed., 1981, Wiley & Sons, N.Y., N.Y., pp. 26-43.
Chemical Abstracts, 93:197666w (1980). *
Stock et al., Cancer Research, Supplement No. 2, 1955, pp. 179 187 and 321. *
Stock et al., Cancer Research, Supplement No. 2, 1955, pp. 179-187 and 321.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996007420A1 (en) * 1994-09-03 1996-03-14 The University Of Nottingham Macrophage stimulating composition comprising a non-ionic surfactant

Also Published As

Publication number Publication date
JPS58146510A (ja) 1983-09-01
DE86122T1 (de) 1983-11-24
DE3370283D1 (en) 1987-04-23
IL67748A (en) 1986-01-31
EP0086122B1 (fr) 1987-03-18
EP0086122A1 (fr) 1983-08-17
IL67748A0 (en) 1983-05-15
CA1188226A (en) 1985-06-04
FR2520619B1 (en)) 1984-04-06
FR2520619A1 (fr) 1983-08-05
JPH0460093B2 (en)) 1992-09-25
ZA83396B (en) 1983-10-26

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